According to the National Health and Nutrition Examination Survey (NHANES III, 1988 to 1994), between one third and one half of men and women in the United States are overweight. In the United States, sixty percent of men and fifty-one percent of women, of the age of 20 or older, are either overweight or obese. In addition, a large percentage of children in the United States are overweight or obese.
The cause of obesity is complex and multi-factorial. Increasing evidence suggests that obesity is not a simple problem of self-control but is a complex disorder involving appetite regulation and energy metabolism. In addition, obesity is associated with a variety of conditions associated with increased morbidity and mortality in a population. Although the etiology of obesity is not definitively established, genetic, metabolic, biochemical, cultural and psychosocial factors are believed to contribute. In general, obesity has been described as a condition in which excess body fat puts an individual at a health risk.
There is strong evidence that obesity is associated with increased morbidity and mortality. Disease risk, such as cardiovascular disease risk and type 2 diabetes disease risk, increases independently with increased body mass index (BMI). Indeed, this risk has been quantified as a five percent increase in the risk of cardiac disease for females, and a seven percent increase in the risk of cardiac disease for males, for each point of a BMI greater than 24.9 (see Kenchaiah et al., N. Engl. J. Med. 347:305, 2002; Massie, N. Engl. J. Med. 347:358, 2002). In addition, there is substantial evidence that weight loss in obese persons reduces important disease risk factors. Even a small weight loss, such as 10% of the initial body weight in both overweight and obese adults has been associated with a decrease in risk factors such as hypertension, hyperlipidemia, and hyperglycemia. Recently it has been shown that considerable weight loss can effectively cure type 2 diabetes (Lim et al, Diabetologia June 2011).
Although diet and exercise provide a simple process to decrease weight gain, overweight and obese individuals often cannot sufficiently control these factors to effectively lose weight. Pharmacotherapy is available; several weight loss drugs have been approved by the Food and Drug Administration that can be used as part of a comprehensive weight loss program. However, many of these drugs have proven to have serious adverse side effects, and have had to be withdrawn again. When less invasive methods have failed, and the patient is at high risk for obesity related morbidity or mortality, weight loss surgery is an option in carefully selected patients with clinically severe obesity. However, these treatments are high-risk, and suitable for use in only a limited number of patients. It is not only obese subjects who wish to lose weight. People with weight within the recommended range, for example, in the upper part of the recommended range, may wish to reduce their weight, to bring it closer to the ideal weight. Thus, a need remains for agents that can be used to effect weight loss in overweight and obese subjects as well as subjects who are of normal weight.
A number of derivatives of peptides deriving from the pro-glucagon molecule have been proposed for use in treatment of obesity and/or diabetes. Pro-glucagon is a precursor peptide of glucagon and several other hormones including oxyntomodulin (OXM) and GLP1 (glucagon-like peptide 1). The present invention is based on the discovery that hybrid peptide molecules containing sequence from both the GLP1 peptide and the glucagon peptide in which specific residues are deleted and/or substituted can be administered to a subject in order to cause decreased food intake, decreased calorific intake, decreased appetite, an increase in energy metabolism, enhanced insulin release and/or carbohydrate tolerance. In many cases such analogues exhibit improved potency and/or longer duration of action and fewer side effects than hybrid molecules based solely on the native residues of GLP1 and/or glucagon.
GLP1 and glucagon may be considered to have opposite effects on circulating glucose concentration. GLP1 is produced in vivo in the intestinal L cell in response to the presence of nutrients in the lumen of the gut. Once in the circulation, native GLP1 has a half-life of only a few minutes in humans due to rapid degradation by the enzyme dipeptidyl peptidase. GLP1 possesses a number of physiological functions including increasing insulin secretion from the pancreas in a glucose-dependent manner, decreasing glucagon secretion from the pancreas, inhibiting gastric emptying and decreasing food intake by increasing satiety. Increased insulin secretion leads to a decrease in circulating glucose concentration.
Glucagon is released in vivo when blood glucose levels fall low and has the activity of causing the liver to convert stored glycogen into glucose which is released into the bloodstream raising blood glucose levels. In this respect the action of glucagon may be regarded as opposite to that of insulin, and because insulin secretion is promoted by GLP1, it may therefore be regarded as having the opposite activity of GLP1. However, the interaction between the various hormones is complex because glucose also stimulates the release of insulin so that newly released glucose in the bloodstream as a result of glycogenlysis can be taken up and used by insulin dependent tissues. It has been proposed that a hybrid molecule with activities at the receptors for both GLP1 and of glucagon may be used for the treatment of type II diabetes (non-insulin dependent diabetes mellitus). Pan et al. discloses a peptide which a GLP1 agonist and a glucagon antagonist (Pan et al. Journal of Biological Chemistry, vol. 281, no. 18, p. 12501-12515, 5 May 2006). Some of the peptides disclosed in Pan et al. also contain sequences derived from exendin-4 which is an animal venom. The half-life of the compounds disclosed in Pan et al. are disappointing and it is proposed that PEGylation may be used to increase the circulatory half-life of the proteins to allow once a week dosing. However, PEGylation may result in a reduced activity due to steric hindrances. Pan et al. suggests that stability may be proved by adding a positive charge at residue 12 or by substituting methionine at position 27 to leucine in an attempt to mitigate oxidative degradation. Runge et al. (British Journal of Pharmacology 2003, vol. 138, p. 787 to 794) discloses a hybrid peptide molecule comprising residues 7 to 20 of GLP1 and residues 15 to 29 of glucagon, and a further hybrid molecule comprising residues 1 to 14 of glucagon and residues 21 to 27 of GLP1.